The interaction between chemokines and their receptors is not in a one - to - one mode. Usually, they can bind to multiple targets to form a complex network system, which can play an important role in a variety of diseases. However, CXCR4 and CXCL12 are quite special as they have a one - to - one ligand - receptor relationship. CXCL12 has a strong chemotactic effect on lymphocytes, and its specific receptor, CXCR4, is one of the several chemokine receptors currently used for the extraction and purification of HIV. Nevertheless, the role of CXCR4 is far more than that; it is involved in various physiological mechanisms in the body, such as hematopoietic function, embryonic development, and the regulation of tumor cell migration and proliferation [2].
The research direction of tumor therapy targeting CXCR4 is quite mature. For example, in the study on PI - 3K - AKT, it was found that in gastric cancer cells, the binding of CXCL12 - CXCR4 activates PI3Kγ, which then binds to its regulatory subunit, thereby activating the expression of downstream signaling molecules of PI3Kγ, such as nuclear factor κB, protein kinase B, extracellular regulated protein kinase 1/2, and mitogen - activated protein kinase [3, 4].
In terms of hematological tumors, as early as 2008, Plerixafor, the world's first CXCR4 antagonist drug, was approved for marketing in Europe and the United States. When used in combination with G - CSF, it can be used in patients undergoing autologous hematopoietic stem cell transplantation to improve the mobilization effect.
CXCR4 not only plays a key role in tumor diseases but also has a close relationship with some immune diseases such as systemic lupus erythematosus, rheumatic - related diseases, and viral diseases like HIV.
In 2019, an academic study included and published by Springer Switzerland Branch suggested that targeted delivery therapy targeting CXCR4 indeed has a good therapeutic effect on tumor diseases. However, the traditional forms based on cell ligands or antibodies still have significant obstacles in the treatment of non - tumor diseases (such as HIV infection). In this research project, the researchers used a chimeric protein (4M5.3X4) formed by fusing a nanobody targeting CXCR4 (NbCXCR4) with an anti - fluorescein (FITC) scFv fragment carrying siRNA. Benefiting from the small molecular size and stability of the nanobody, this chimeric protein can accurately and selectively deliver siRNA to CXCR4 - positive cells and release it there.
Design of 4M5.3X4 Chimera Targeting CXCR4+ [5]
To evaluate the inhibitory effect of this chimera on targeted siRNA delivery, the research team infected human T lymphoma cells (SUP - T1) with the NL4 - 3 strain of HIV - 1 for 24 hours, then targeted 4M5.3X4 to the positive cells and released siRNA. Detection results showed that the HIV replication rate was reduced by approximately 80% in the T lymphocyte line (p ≤ 0.05). Moreover, the research team found that only the 4M5.3X4 chimeric protein could inhibit the infection of NL4 - 3, while other chimeric proteins used in the control experiment had no inhibitory effect. More importantly, this chimera had an inhibition rate of over 90% on the recombinant strain CRF02_AG of the HIV - 1 isolated strain 01PTHDECJN, and an inhibition rate of about 65% on the HIV - 2 isolated strain 03PTHCC6.
Inhibitory Effect of 4M5.3X4 Chimera on NL4 - 3 [5]
From these studies, we can easily see the great potential of CXCR4 in the development of various new tumor treatment strategies. At the same time, it is not difficult to perceive from the above research project that CXCR4 can also contribute to the development of treatment strategies for HIV infection, and even extend to the research and development of treatment strategies for various other non - tumor diseases, such as eye diseases and liver diseases.
NBLST focuses on the development, modification, and application of nanobodies. It aims to provide high - quality and cost - effective nanobody CRO services for a large number of scientific research institutions and biopharmaceutical enterprises. Currently, the launched chemokine nanobodies include IL - 2, IL - 18, and IL - 18 Binding Protein, which are available for direct purchase by customers. Additionally, it can also provide custom - made services for any other nanobodies.